Rapamycin derivatives

Details Rapamycin derivatives Rapamycin derivatives

1995-03-06

1997-08-26

Bond, Robert T.

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Having -c-, wherein x is chalcogen, bonded directly to...

540456, A61K 31395, C07D26700

Patent

active

056611560

DESCRIPTION:

BRIEF SUMMARY
BACKGROUND OF THE INVENTION

This invention relates to rapamycin derivatives, pharmaceutical compositions comprising such derivatives, and methods of treatment of pathogenic fungi, methods of inducing immunosuppression and methods of treating carcinogenic tumors utilizing such rapamycin derivatives.
Rapamycin is a naturally occurring macrocyclic triene antibiotic which can be produced by culturing an organism in an aqueous nutrient medium. Its structure may be illustrated as follows: ##STR2##
At least one rapamycin-producing strain of Streptomyces hygroscopius was deposited with the Northern Utilization and Research Division, Agricultural Research Service, U.S. Department of Agriculture, Peoria, Ill., U.S.A. under accession number NRRL 5491. Rapamycin, and methods for its preparation by culturing NRRL 5491 are disclosed by U.S. Pat. No. 3,929,992, issued Dec. 30, 1975, the entire disclosure of which is hereby incorporated by reference.


SUMMARY OF THE INVENTION

This invention relates to novel rapamycin derivatives of the formula: ##STR3## wherein: R.sup.1 is selected from the group consisting of .dbd.O, (--OR.sup.6,H) and (H,H); that R.sup.2 is (H,H) when R.sup.1 is (--OR.sup.6,H) or .dbd.O; --H, --C(.dbd.O)R.sup.7, --C(.dbd.O)OR.sup.7, --C(.dbd.O)NHR.sup.7, and --C(.dbd.S)OR.sup.7 ; alkyl; and -C.sup.6 cycloalkyl, aryl groups, and heterocyclic groups; (a) R.sup.2 is other than .dbd.O, (b) R.sup.3 is other than H, and (c) R.sup.5 is other than H.
This invention also relates to a pharmaceutical composition comprising an effective amount of one or more compounds of Formula II and a pharmaceutically acceptable carrier or diluent.
This invention also relates to a method of inhibiting the growth of pathogenic fungi in a human or other animal in need thereof which comprises administering an effective, non-toxic amount of one or more compounds of Formula II to such human or other animal.
This invention also relates to a method of inducing immunosuppression in a human or other animal in need thereof which comprises administering an effective, non-toxic amount of one or more compounds of Formula II to such human or other animal.
In addition, this invention relates to a method of treating carcinogenic tumors in a human or other animal comprising administering an effective, non-toxic amount of one or more compounds of Formula II to such human or other animal.
Still further, this invention relates to compounds of Formula III which are useful as intermediates for preparing compounds of Formula II: ##STR4## where R' is --(S)COPh, where Ph is phenyl; R" is selected from the group consisting of H and --(S)COPh,
Still further, this invention relates to a method of preparing novel compounds of Formula II from intermediates of Formula III.


DETAILED DESCRIPTION OF THE INVENTION

When any substituent or variable (e.g., aryl, alkoxyl, R.sup.1, R.sup.2, R.sup.3, R.sup.5, R.sup.6, etc.) occurs more than one time in the formula of any of the compounds of Formula II, such variable or substituent definition on each occurrence is independent of its definition at every other occurrence, unless otherwise indicated. Combinations of substituents and/or variables are in a constituent of the compounds of the invention are permissible only if such combinations result in a stable compound.
The parenthetical nomenclature used in the definition of substituents such as R.sup.1 (e.g., (H, OR.sup.6) is intended to reflect the substituents on both valences of the relevant atom. The invention is not limited to particular isomers and the order of moieties in the parentheses does not suggest a particular configuration.
As used herein, except where otherwise noted, the term "alkyl" is intended to include both branched- and straight-chain saturated and unsaturated aliphatic hydrocarbon groups. Preferred alkyl groups have one to six carbon atoms, unless otherwise noted. Such alkyl group may be optionally substituted by one or more members independently selected from the group consisting of aryl, hydroxyl, C.sub.1 -C.sub.6 alkoxyl, acyloxy, amino, N-

REFERENCES:
patent: 5023263 (1991-06-01), Von Burg
patent: 5130307 (1992-07-01), Failli et al.
patent: 5284877 (1994-02-01), Organ et al.

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